Following uniocular anterior chamber inoculation of the KOS strain of HSV-1 in euthymic BALB/c mice, extensive virus infection accompanied by a massive inflammatory response is observed in the anterior segment of the injected eye. However, in spite of the virus infection in the anterior segment, virus does not infect the retina of the inoculated eye. In contrast, the retina of the uninoculated eye becomes infected with virus beginning on or about day 7 p.i., and the retina of this eye is destroyed by 14 days p.i. Although there is mild anterior uveitis, the anterior segment of the uninoculated eye does not become infected. The overall goal of the studies proposed in this application is to elucidate the pathogenesis of HSV-1 infection in the injected eye, the brain, and the uninjected eye following uniocular anterior chamber inoculation of HSV-1. Three specific aims will define (1) the mechanism by which direct anterior-to-posterior spread of the KOS strain of HSV-1 is prevented following uniocular anterior chamber inoculation of BALB/c mice, (2) the mechanism which prevents virus that has spread to the brain in euthymic BALB/c mice from infecting the optic nerve and retina of the injected eye, and (3) the role of T cells and cytokines during HSV-1 infection of the retina of the uninoculated eye. Information about early protection in the injected eye following anterior chamber inoculation may provide clues about why patients with HSV-1 keratitis, many of whom also have viral anterior uveitis, do not normally develop retinitis in the afflicted eye. Information about limitation of virus spread in the hypothalamus may provide insight into why virus that reaches the brain in pathways other than the trigeminal may be unable to spread to the optic nerve and retina and may help to explain why such a small number of patients with HSV-1 develop retinitis. Studies of how T cells and cytokines contribute to retinitis once virus has infected an eye may aid in design of specifically-targeted therapies to modulate an established infection.